Tight glycernic control is now a standard goal of most patients with diabetes. The consequence is that, while the progression of long-term complications has been reduced, the risk of iatrogenic insulin-induced hypoglycemia as a complication has increased. Physical activity dramatically heightens this risk due to the associated increase in insulin action. Exercise in healthy subjects is characterized by both an increase in the glycemic threshold for counterregulation and an amplification in the magnitude of the counterregulatory response. These are favorable adaptations that protect against hypoglycemia. This robust response to prevent hypoglycemia can be impaired in people with diabetes. Despite the essential role that the counterregulatory response plays during exercise, the mechanism for its increased effectiveness, the factors responsible when it fails, and the means to correct it when it fails are poorly understood. The proposed studies are a continuation of experiments conducted under the auspices of this grant that have identified novel and sensitive mechanisms for glucose sensing and the presence of insulin sensitive neural pathways that modulate systemic metabolism. The experiments will define the importance of specific sites involved in sensing a decrement in glucose during exercise and the means by which glucose counterregulatory responses are amplified by exercise. Identifying mechanisms for sustaining endogenous glucose production (EGP) in people with impaired counterregulatory responses is a key for prevention of insulin-induced hypoglycemia. Intraportal infusion of the purine nucleotide precursor, 5'-aminoimidazole-4-carboxamide-l-Dribofuranoside (AICAR) has provided insight into one potential mechanism. Intraportal AICAR stimulates EGP independent of changes in counterregulatory hormones and is effective even in the presence of elevated insulin levels that would normally completely suppress EGP. Hepatic actions of AICAR have important implications for understanding physiological regulation of liver function under conditions that, like exercise, are characterized by increased EGP. Moreover, the ability of AICAR to act in the presence of high insulin suggests that it, or a compound that works through a related mechanism, may be effective as a means of combating insulin-induced hypoglycemia. Proposed studies use methodology for well-controlled experimentation to be carried out in vivo. Studies will be conducted in chronically catheterized, 18 h fasted conscious dogs using surgical and pharmacological techniques to perturb or control the system. Hormonal, autonomic, and glucose metabolic responses will be measured using sensitive isotopic ([3-3H] glucose, 2H:O, [U-14C] glucose) and arteriovenous difference (liver, gut, pancreas, kidney, limb) techniques. The protocols in this proposal will define mechanisms for the heightened role of the nervous system in mediating responses to hyperinsulinemia and hypoglycemia during physical exercise. There will be an emphasis on understanding physiological and pharmacological mechanisms that counter insulin-induced hypoglycemia. The specific aims are to: (1) identify the sites responsible for the amplified glucose counterregulatory response to exercise; (2) test whether insulin sensitive neural pathways modulate the response to exercise; and (3) characterize the actions of AICAR on the liver and brain and determine whether this compound or a related one might be effective in counteracting insulin-induced hypoglycemia.